title: Increased ectodomain shedding of lung epithelial cell adhesion molecule 1 as a cause of increased alveolar cell apoptosis in emphysema.
abstract: BACKGROUND
  Alveolar epithelial cell apoptosis and protease/antiprotease imbalance based proteolysis play central roles in the pathogenesis of pulmonary emphysema but molecular mechanisms underlying these two events are not yet clearly understood. Cell adhesion molecule 1 (CADM1) is a lung epithelial cell adhesion molecule in the immunoglobulin superfamily. It generates two membrane associated C terminal fragments (CTFs), αCTF and βCTF, through protease mediated ectodomain shedding.
  
  
  OBJECTIVE
  To explore the hypothesis that more CADM1-CTFs are generated in emphysematous lungs through enhanced ectodomain shedding, and cause increased apoptosis of alveolar epithelial cells.
  
  
  RESULTS
  Western blot analyses revealed that CADM1-CTFs increased in human emphysematous lungs in association with increased ectodomain shedding. Increased apoptosis of alveolar epithelial cells in emphysematous lungs was confirmed by terminal nucleotide nick end labelling (TUNEL) assays. NCI-H441 lung epithelial cells expressing mature CADM1 but not CTFs were induced to express αCTF both endogenously (by shedding inducers phorbol ester and trypsin) and exogenously (by transfection). Cell fractionation, immunofluorescence, mitochondrial membrane potentiometric JC-1 dye labelling and TUNEL assays revealed that CADM1-αCTF was localised to mitochondria where it decreased mitochondrial membrane potential and increased cell apoptosis. A mutation in the intracytoplasmic domain abrogated all three abilities of αCTF.
  
  
  CONCLUSIONS
  CADM1 ectodomain shedding appeared to cause alveolar cell apoptosis in emphysematous lungs by producing αCTF that accumulated in mitochondria. These data link proteolysis to apoptosis, which are two landmark events in emphysema.
authors.affiliation: Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Graduate School of Biomedical Sciences, Hiroshima University, , Hiroshima, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Mimae
authors.forename: Man
authors.initials: M
authors.lastname: Hagiyama
authors.forename: Takao
authors.initials: T
authors.lastname: Inoue
authors.forename: Azusa
authors.initials: A
authors.lastname: Yoneshige
authors.forename: Takashi
authors.initials: T
authors.lastname: Kato
authors.forename: Morihito
authors.initials: M
authors.lastname: Okada
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Murakami
authors.forename: Akihiko
authors.initials: A
authors.lastname: Ito
mesh_terms: D056809:Alveolar Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D017209:Apoptosis / Q000276:immunology*; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007128:Immunoglobulin Fragments / Q000378:metabolism*; D007136:Immunoglobulins / Q000276:immunology / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D011237:Predictive Value of Tests; D059748:Proteolysis; D011656:Pulmonary Emphysema / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D012307:Risk Factors; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D012907:Smoking / Q000009:adverse effects
chemical_list: D015415:Biomarkers; C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007128:Immunoglobulin Fragments; D007136:Immunoglobulins; D018799:Intercellular Adhesion Molecule-1
keywords: Airway Epithelium; Emphysema